Fluorouracil/Leucovorin Maintains Leading Role, Results of Three-Drug Regimens Are Pending

ROCHESTER, Minnesota—Summarizing cooperative group approaches to adjuvant treatment of colorectal cancer, Charles Erlichman, MD, noted: "Treatment for stage II colon cancer remains controversial. Treatment for stage III colon cancer should be fluorouracil (5-FU)/leucovorin. Treatment for stage III rectal cancer should be radiation plus fluorouracil/leucovorin. The results of three-drug regimens are pending, as are data on the role of COX-2 inhibitors and of targeted agents such as epidermal growth factor receptor (EGFR) or tyrosine kinase inhibitors." Dr. Erlichman is professor of oncology, Mayo Clinic, Rochester, Minnesota.

The current standard of care for stage II colon cancer is based on several major studies. "The International Multicentre Pooled Analysis of Colon Cancer Trial (IMPACT) analysis, which I was involved in, compared 5-FU/leucovorin to observation and found a nonsignificant 2% difference in overall survival," Dr. Erlichman said. Similarly, a study of insurance claims for over 3,700 stage II patients in New York, reported by Schrag et al in a presentation at the American Society of Clinical Oncology Meeting in 2001 (ASCO abstract 488), found that adjuvant therapy improved 5-year survival by only 2%, from 72% to 74%. The result has been a lack of agreement, according to Dr. Erlichman, with the National Surgical Adjuvant Breast and Bowel Project (NSABP) recommending adjuvant chemotherapy for all Dukes stage B patients and the IMPACT trial advising no adjuvant therapy for patients with stage II colon cancer.

Age Alone Is No Barrier

Dr. Erlichman said that 5-FU/leucovorin is the current standard adjuvant treatment and increases 5-year survival from about 50% to about 70% in mixed populations of stage II and stage III colon cancer. A pooled analysis drawn from several phase III trials looking at age concluded that age alone is no barrier to adjuvant chemotherapy. Dr. Erlichman pointed out, however, that the mixture of stage II and stage III patients in these studies makes adjuvant chemotherapy for stage II colon cancer controversial.

"Because of this controversy, intergroup study C9581 was started with a plan to treat 2,100 patients with stage II colon cancer. About 1,700 patients have been enrolled on the study. The drug supply ran out in June 2002 due to a negative study in stage III disease. Patients are still being followed, but we will have to wait much longer than was originally planned to be able to ferret out whether this drug has any utility," Dr. Erlichman said.

Newer Regimens Tested

The VICTOR study being conducted in Europe is examining the effect of a COX-2 inhibitor on colon cancer. The trial has enrolled 200 of a planned 700 patients with stage II or stage III colon cancer, Dr. Erlichman reported. "The idea is to put everybody on the trial, and if there are enough patients, you will get answers."

Patients in this study can receive adjuvant treatment or not and then are randomized to placebo or rofecoxib (Vioxx) for 2 years or to placebo or rofecoxib for 5 years. Endpoints are survival and number of polyps developed at 2 years. "The effect on polyps may be an early indicator of whether there is any benefit to this treatment as a preventive approach," Dr. Erlichman said.

The next step in design of adjuvant trials will be regimens combining irinotecan (CPT-11, Camptosar) and oxaliplatin (Eloxatin), and regimens integrating the novel targeted agents.

In adjuvant treatment of rectal cancer, Dr. Erlichman said that standard of care should be either preoperative or postoperative radiotherapy with a 5-FU-based chemotherapy regimen. A planned Eastern Cooperative Oncology Group trial will randomize about 200 patients to either preoperative or postoperative radiation then to FU/leucovorin plus either irinotecan or oxaliplatin, or to 5-FU/leucovorin alone.